TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia

Brain. 2022 Sep 14;145(9):3095-3107. doi: 10.1093/brain/awac123.

Luis Carlos Tábara ¹, Fatema Al-Salmi ², Reza Maroofian ³, Amna Mohammed Al-Futaisi ⁴, Fathiya Al-Murshedi ⁴, Joanna Kennedy ² ⁵, Jacob O Day ² ⁶, Thomas Courtin ⁷, Aisha Al-Khayat ⁸, Hamid Galedari ⁹, Neda Mazaheri ⁹, Margherita Protasoni ¹, Mark Johnson ¹, Joseph S Leslie ², Claire G Salter ², Lettie E Rawlins ² ¹⁰, James Fasham ² ¹⁰, Almundher Al-Maawali ⁴, Nikol Voutsina ², Perrine Charles ⁷, Laura Harrold ², Boris Keren ⁷, Edmund R S Kunji ¹, Barbara Vona ¹¹, Gholamreza Jelodar ¹², Alireza Sedaghat ¹³, Gholamreza Shariati ¹⁴, Henry Houlden ³, Andrew H Crosby ², Julien Prudent ¹, Emma L Baple ² ¹⁰

Affiliations

1 Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK.
2 Level 4, RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter EX2 5DW, UK.
3 UCL Queen Square Institute of Neurology, University College London, London WC1E 6BT, UK.
4 Genetic and Developmental Medicine Clinic, Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat 123, Oman.
5 Clinical Genetics, University Hospitals Bristol, Bristol BS2 8EG, UK.
6 Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK.
7 Département de génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75019 Paris, Sorbonne Université, France.
8 Department of Biology, College of Science, Sultan Qaboos University, Muscat, Oman.
9 Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
10 Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital (Heavitree), Exeter EX1 2ED, UK.
11 Department of Otolaryngology-Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, Germany.
12 Pediatric Neurology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
13 Health Research Institute, Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
14 Department of Medical Genetic, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Ahvaz, Iran.

PMID: 35718349 DOI: 10.1093/brain/awac123

Abstract

The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria-endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.

Keywords

TMEM63C; endoplasmic reticulum/ER; hereditary spastic paraplegia/HSP; mitochondria; mitochondria-ER contact sites/MERCs.

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